Expandable implantable conduit

ABSTRACT

An expandable valved conduit for pediatric right ventricular outflow tract (RVOT) reconstruction is disclosed. The valved conduit may provide long-term patency and resistance to thrombosis and stenosis. The valved conduit may enlarge radially and/or longitudinally to accommodate the growing anatomy of the patient. Further, a method is disclosed for the manufacture of the valved conduit based in part on a plastically deformable biocompatible polymer and a computer-optimized valve design developed for such an expandable valved conduit.

CLAIM OF PRIORITY

This application is a U.S. national stage filing under 35 U.S.C. § 371of International Application No. PCT/US2014/021814 filed Mar. 7, 2014entitled “EXPANDABLE IMPLANTABLE CONDUIT,” which claims priority of U.S.Provisional Application No. 61/851,487 filed on Mar. 8, 2013 entitled“Expandable Valve Conduit for Pediatric Right Ventricular Outflow Tract(RVOT) Reconstruction”, the disclosures of which are incorporated hereinby reference in their entirety.

BACKGROUND

Conduit selection for right ventricle outflow tract (“RVOT”)reconstruction presents a challenge in the treatment of many congenitalheart diseases including tetralogy of Fallot with pulmonary atresia,truncus arteriosus, transposition of great arteries with pulmonarystenosis, congenital aortic stenosis/insufficiency, and variants of suchconditions. After the invention of the cryopreservation process in early1980s, and especially with the increased availability of a wide range ingraft sizes, homografts have become the conduit of choice for physiciansperforming RVOT reconstruction procedures. Such homografts, in manyinstance, may be used to replace Dacron conduit-mounted stentedglutaraldehyde-treated porcine aortic valve heterografts. However,longitudinal studies have demonstrated that homografts may also requireconduit replacement due to stenosis, shrinkage, calcification, andinsufficiency, especially for younger patients.

Recently, xenograft designs have been evaluated for RVOT reconstruction.Non-limiting examples of such xenografts may includeglutaraldehyde-fixed porcine aortic valves and roots, andglutaraldehyde-fixed segments of bovine jugular veins including venousvalves. Although the anatomical shape of porcine aortic valves may proveuseful in RVOT procedures, stenosis and calcification issues may stillpersist when such xenografts are implanted in children. Similarly, earlyfibrotic rind formation at the distal anastomosis, as well assignificant conduit dilation and regurgitation may occur following theuse of the bovine jugular veins. Thus, allografts and xenografts mayprove to be insufficient replacements in RVOT procedures due to theirpoor hemodynamic performance and recurrent stenosis/insufficiency,especially in very young patients. As a result, multiple RVOT surgeriesmay be required until the pediatric patient reaches adulthood.

Implanted artificial (that is, non-biological) valves may require fewerreplacement surgeries than valves having a biological origin. However,such artificial valves may require significant anticoagulant therapy,especially for valves placed in the pulmonary blood stream.Additionally, replacement artificial valves for use inpediatric/neonatal populations may be limited due to the need to customdesign the valves based on intensive bioengineering studies. It may beappreciated, therefore, that there is a need for valved conduits withextended durability, especially for younger patients.

An expanded polytetrafluoroethylene (hereafter, ePTFE) valved conduitfor pediatric RVOT reconstruction may include a valve design based onthe surgical experience of a physician, or the results from acomputer-optimization routine specific for non-expansible conduits.

Such non-expansible conduits can provide good functionality andresistance to thrombosis, stenosis, and calcification. However, thenon-expansible conduit may not be capable of accommodating the changesin anatomical structures during patient growth. Somatic growth inpediatric patients can result in the need for replacement of implantedheart valves due to stenosis and other complications if the conduit or avalved conduit is not able to accommodate the anatomic or physiologicalchanges due to patient growth.

At present, there appears to be no conduits for the reconstruction of apediatric patient's right ventricular outflow tract (RVOT) havinglong-term patency, a functional valve, and no thrombogenicity.Anti-thrombogenic materials and optimal valve designs can produce goodinitial results. However, young children may quickly outgrow theimplanted conduits and may require reoperation and replacement. To date,only tissue-engineered conduits or valved conduits have been proposed toaccommodate patient growth, but these solutions are time- andcost-intensive and still generally unproved for long-term functionality.

SUMMARY

In some embodiments, an implantable device may include a conduitcomposed of a plastically deformable material having a yield strength ofabout 0.1 MPa to about 4 MPa and an ultimate tensile strength greaterthan about 4 MPa.

In some embodiments, a valved conduit may include a conduit and a valvestructure disposed therein, in which the conduit is composed of at leastone plastically deformable material having a yield strength of about 0.1MPa to about 4 MPa and an ultimate tensile strength greater than about 4MPa.

In some embodiments, a method of fabricating a valved conduit composedof a plastically deformable material for implantation into an animal mayinclude obtaining at least one datum dependent at least in part on oneor more anatomical structures or physiological functions of the animal,determining an initial radial dimension of the valved conduit, anddetermining an at least one expansion measurement for the conduitdependent at least in part on a change in the one or more anatomicalstructures or physiological functions. The plastically deformablematerial may have a yield strength of about 0.1 MPa to about 4 MPa andan ultimate tensile strength greater than about 4 MPa. The embodimentsfurther may include calculating, using a computing device, an initialflow metric representative of a fluid flowing through an initial valvedconduit having physical characteristics of an initial mathematical modelof the valved conduit based at least in part on the at least one datum,the initial radial dimension, and an at least one plasticity property ofthe plastically deformable material. Additionally, the embodiments mayinclude calculating, using the computing device, an at least second flowmetric representative of the fluid flowing through a second valvedconduit having physical characteristics of an at least secondmathematical model of the valved conduit, based at least in part on theat least one datum, the expansion measurement, and the at least oneplasticity property. Further, the embodiments may include calculating,using the computing device, a deformation metric based at least in parton the initial flow metric and the at least one second flow metric andfabricating the valved conduit based, at least in part, on the physicalcharacteristics of the initial mathematical model of the valved conduitif the deformation metric is greater than or equal to an acceptancevalue.

In some embodiments, a method of replacing a first valved conduitcomposed of a plastically deformable material implanted in an animal mayinclude contacting an inner surface of the first valved conduit with anexpansion device, causing the expansion device to expand, therebyradially increasing at least a portion of the first valved conduit,introducing a second valved conduit within at least a portion of thefirst valved conduit, and causing the second valved conduit to expandwithin the at least portion of the first valved conduit, in which theplastically deformable material has a yield strength of about 0.1 MPa toabout 4 MPa and an ultimate tensile strength greater than about 4 MPa.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an embodiment of a cross-section view of anexpandable valved conduit with bicuspid leaflets prior to expansion inaccordance with the present disclosure.

FIGS. 2A and 2B illustrate embodiments of an expandable valved conduitin an open and a closed position, respectively, in accordance with thepresent disclosure.

FIGS. 3A and 3B illustrate an embodiment of a model of a 20 mm conduitin mesh form, and after being converted to a solid 3D model,respectively, in accordance with the present disclosure.

FIG. 4 illustrates an embodiment of a computational fluid dynamicssimulation of flow through a 20 mm diameter curved conduit in thephysiologic position in accordance with the present disclosure.

FIG. 5 is a flow chart of a method for fabricating an expandable valvedconduit from a plastically deformable material in accordance with thepresent disclosure.

FIG. 6 is a flow chart of a method for replacing a first expandablevalved conduit with a second expandable valved conduit in accordancewith the present disclosure.

FIGS. 7A and 7B are stress/strain curves obtained for two exemplaryplastically deformable materials, respectively, that may be used in avalved conduit in accordance with the present disclosure.

DETAILED DESCRIPTION

Before the present methods are described, it is to be understood thatthis invention is not limited to the particular systems, methodologiesor protocols described, as these may vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to limit the scope ofthe present disclosure which will be limited only by the appendedclaims.

For the purpose of this disclosure, the term “plastically deformablematerial” means a material that may change its shape, size, or bothshape and size in response to a deforming force placed thereon, andwhich does not fully recover its original shape, size, or both shape andsize once the deforming force has been removed.

For the purpose of this disclosure, the term “elastic material” means amaterial that may change its shape, size, or both shape and size inresponse to a deforming force placed thereon, and which recovers itsoriginal shape, size, or both shape and size once the deforming forcehas been removed.

For the purpose of this disclosure, the term “deforming force” means aforce that, when applied to a material, will result in a change in theshape, size, or both shape and size of the material.

For the purpose of this disclosure, the term “yield strength” means thesmallest deforming force that, when applied to a material, will resultin a non-recoverable change in the shape, size, or both shape and sizeof the material.

For the purpose of this disclosure, the term “ultimate tensile strength”means the smallest deforming force that, when applied to a material,will result in a break or failure of the material.

For the purpose of this disclosure, the term “anatomic compliance” or“anatomically compliant” means the capability of a material or structureto change size, shape, or size and shape in response to the changes inanatomical structures (resulting from patient growth) within a patientin which the material or structure has been implanted.

For the purpose of this disclosure, the term “physiological compliance”or “physiologically complaint” means the capability of a material orstructure to maintain its structural integrity under normalphysiological conditions. As such, a physiologically compliant materialor device may exhibit sufficient elasticity to allow the material ordevice to expand and return to its original shape under normalphysiological conditions. For example, a physiologically compliantdevice designed to be incorporated into the circulatory system mayexhibit elasticity similar to healthy blood vessels under normalphysiological conditions.

Various embodiments of the invention are directed to implantableconduits that are physiologically compliant under physiologicalconditions but that can also plastically deform under non-physiologicalconditions allowing the conduit to be expanded radially and/orlongitudinally. Such deformation allows for the conduit to be expandedto suit the patient's needs. For example, on implantation in a child orjuvenile patient, such implantable conduits may have a firstphysiologically appropriate radius consistent with the patient's age,size, or physical condition. As the patient grows, the radius of theimplantable conduit may be increased by applying sufficient radial forceusing, for example, a balloon catheter, to cause the implantable conduitto deform taking on a second physiologically appropriate radius.Alternatively, the radius of the implantable conduit may increase to alarger physiologically appropriate radius as a result of anatomicaland/or physiological forces associated with patient growth as thepatient grows. After stable expansion, the conduit will continue to bephysiologically compliant under physiological conditions. Thus, theexpandable conduit may be deformed to expand or grow with the patient,thereby reducing the need to invasive surgeries to replace the conduitas patient needs change.

The expandable conduit disclosed herein may also be useful for replacingpreviously implanted homograft or other conduits that have becomedysfunctional or insufficient. Additional uses for the disclosed conduitmay include applications related to the treatment of pediatric and adultdisorders, including other areas of the heart or more generally to otherparts of the body. Some examples of additional uses may further includeprocedures associated with repair of pediatric left ventricular outflowtract (LVOT) pathologies as well as for use in Fontan/Kreutzerprocedures. It may be further understood that such expandable conduitsmay find use in non-human animals for veterinary purposes as well.

The expandable conduits of various embodiments may be composed, at leastin part, of one or more biocompatible polymers that are plasticallydeformable under some conditions and are elastic under other conditions.

In particular, under some physiological conditions the conduit may beelastic. Typical blood flow exerts up to about 0.02 MPa of pressure onthe blood vessels under stress conditions or high intensity activity.Under such conditions, the natural elasticity of the blood vessels allowthem to radially expand to allow for increased blood flow. The bloodvessels return to their normal diameter under lower steady statepressures. The expandable conduits of various embodiments exhibitsimilar elasticity. For example, in some embodiments, the conduits maybe elastic at pressures of from about 0.0001 MPa to about 0.02 MPa,about 0.0001 MPa to about 0.015 MPa, about 0.0001 MPa to about 0.004MPa, or any individual pressure or range encompassed by these exampleranges.

The conduits of such embodiments may be deformable at non-physiologicalpressures greater than those described above. Therefore, as patientneeds change, such conduits may be enlarged by applying pressures inexcess of what would be produced by, for example, natural blood flow. Insuch embodiments, an expandable conduit that is elastic at the pressuresdescribed above may be radially deformed by use of a balloon catheter orother device. In various embodiments, such conduits may be plasticallydeformable at pressures (or yield strength) of, for example, about 0.05MPa to about 2.5 MPa, about 0.3 MPa to about 2.5 MPa, about 0.1 MPa toabout 4 MPa, or any range or individual pressure encompassed by theseexample ranges. It may be understood that specific yield strength valuesdisclosed herein are not to be considered limiting, and that someembodiments of expandable conduits may include those having yieldstrength values greater than about 4 MPa. Conduits having such largeyield strength values may be useful for use with expansion devices, suchas balloon catheters, capable of exerting radial pressures greater thanabout 4 MPa.

In particular embodiments, the conduits may exhibit a yield strengththat allows for expansion under certain physiological conditions. Forexample, in some embodiments, the expandable conduit may exhibit a yieldstrength of about 0.004 MPa to about 0.02 MPa, about 0.015 MPa to about0.04 MPa, or any range or individual yield strength encompassed by theseexample ranges. Because such pressures are rarely achieved underphysiological conditions, such conduits may slowly expand afterimplantation, and this slow expansion may allow for the conduit toexpand with the growth of the patient reducing the need for manualexpansion using a balloon catheter or other device.

In each of the embodiments described above, the conduits may typicallyexhibit an ultimate tensile strength that is greater than about 2.5 MPa,3.0 MPa, 4.0 MPa, or 5.0 MPa. Such ultimate tensile strengths ensurethat the conduit does not burst either under physiological conditions orat deformation pressures. In some alternative embodiments, a conduit mayexhibit an ultimate tensile strength that is about 1 MPa greater thanits yield strength. Non-limiting examples of such conduits may include aconduit having a yield strength of about 0.02 MPa and an ultimatetensile strength greater than about 1.0 MPa, a conduit having a yieldstrength of about 0.3 MPa and an ultimate tensile strength greater thanabout 1.3 MPa, a conduit having a yield strength of about 1.0 MPa and anultimate tensile strength greater than about 2.0 MPa, a conduit having ayield strength of about 2.5 MPa and an ultimate tensile strength greaterthan about 3.5 MPa, and a conduit having a yield strength of about 4 MPaand an ultimate tensile strength greater than about 5 MPa.

Conduits fabricated from materials characterized by such combinations ofyield strengths and ultimate tensile strengths may be implanted intovascular structures using sutures. It may be understood that additionalstrength characteristics of the conduits may be related to the sutureretention strength. In some non-limiting examples, the suture retentionstrength may be greater than or about equal to 50 gram force (about 0.5N). In some alternative non-limiting examples, the suture retentionstrength may be greater than or about equal to 80 gram force (about 0.8N).

Embodiments of conduits having yield strengths and ultimate tensilestrengths as disclosed above may be either compressed or expanded. Suchcompression or expansion may be provided along either the radialdimension or along the longitudinal dimension. In some examples, aconduit may exhibit a radial expandability of about 20% to about 200%above its initial pre-expansion radius. Examples of such percent radialexpandability may include, without limitation, about 20%, about 40%,about 50%, about 100%, about 150%, and about 200% above the initialpre-expansion radius, and ranges between any two of these values(including endpoints). In some examples, a conduit may exhibit a radialcompressibility of about 33% to about 83% of the initial pre-compressionradius. Examples of such percent radial compressibility may include,without limitation, about 33%, about 40%, about 45%, about 50%, about60%, about 70%, about 80%, and about 83% of the initial pre-compressionradius, and ranges between any two of these values (includingendpoints). In some alternative examples, a conduit may exhibit alongitudinal expandability of about 5% to about 500% above the initialpre-expansion length. Examples of such percent longitudinalexpandability may include, without limitation, about 5%, about 10%,about 50%, about 100%, about 150%, about 200%, about 300%, about 400%,and about 500% above the initial pre-expansion length, and rangesbetween any two of these values (including endpoints). In someadditional examples, a conduit may exhibit a longitudinalcompressibility of about 33% to about 91% of the initial pre-compressionlength. Examples of such percent longitudinal compressibility mayinclude, without limitation, about 33%, about 40%, about 50%, about 60%,about 70%, about 80%, about 90%, and about 91% of the initialpre-compression length, and ranges between any two of these values(including endpoints).

Embodiments of the above-disclosed conduit, possessing such elastic andplastic properties, may not be limited to any particular material,combination of materials, shape, size, or manner of manufacture.Non-limiting examples of such conduits may include other usefulcharacteristics as disclosed below. The properties described above canbe achieved using any means available in the art. For example, in someembodiments, materials with yield strengths of, for example, about 0.05MPa to about 2.5 MPa, about 0.1 MPa to about 2.0 MPa, about 0.1 MPa toabout 1.5 MPa, or any range or individual pressure encompassed by theseexample ranges, can be manufactured into conduits.

In some embodiments, the expandable conduit may be composed of one ormore biocompatible materials, and in certain embodiments, thebiocompatible material may be a fluoropolymer. Non-limiting examples ofsuch biocompatible materials may include polytetrafluoroethylene,expanded polytetrafluoroethelyne (ePTFE), polyester, polyethyleneterephthalate, polydimethylsiloxane, polyurethane, and/or combinationsof those materials. Such biocompatible polymers may also becharacterized by an internode distance (IND), a measure of an averagedistance between nodes formed in a polymer network. In some examples,the biocompatible material used in expandable conduits may have aninternode distance of about 10 μm to about 40 μm. In some alternativeembodiments, the biocompatible material may have an internode distanceof less than 200 μm. Examples of such an internode distance may include,without limitation, about 20 μm, about 40 μm, about 60 μm, about 80 μm,about 100 μm, about 120 μm, about 140 μm, about 160 μm, about 180 μm,about 200 μm, and ranges between any two of these values (includingendpoints).

In various embodiments, such materials may have a density less thanabout 2 g/mm³. In some examples, the material may have a density ofabout 0.2 g/mm³ to about 2 g/mm³. In some alternative examples, thematerial may have a density of about 0.2 g/mm³ to about 0.5 g/mm³.Examples of such material density may include, without limitation, about0.2 g/mm³, about 0.4 g/mm³, about 0.6 g/mm³, about 0.8 g/mm³, about 1.0g/mm³, about 1.5 g/mm³, about 2.0 g/mm³, and ranges between any two ofthese values (including endpoints).

In some embodiments, the expandable conduit may be made of a polymerthat has been coated with material having useful biomedical properties.In some additional embodiments, the conduit may incorporate bio-activecoatings. Non-limiting examples of such bio-active coatings may includeone or more anti-coagulant materials. Non-limiting examples of ananti-coagulant material may include a coumarin, heparin, a heparinderivative, a Factor Xa inhibitor, a direct thrombin inhibitor,hementin, sintered porous titanium microspheres, and/or combinations ofthose materials.

In some additional embodiments, the expandable conduit may be fabricatedfrom a physically pre-treated material. Physical pre-treatment of thematerial may include longitudinal mechanical compression with heating.Further, additional material may be added during the pre-treatmentprocess. The yield strength of a conduit fabricated from suchpre-treated materials may depend on the final length or radius to whichthe conduit is expanded. For example, a conduit expanded eitherlongitudinally or radially up to the original material length or radius(that is, length or radius of the material prior to compression/heating)may have a yield strength much less than that of the original material.As an example, the original material of a conduit may have a yieldstrength of about 10 MPa, but a conduit comprising such pre-treatedmaterial may have a yield strength of about 1 MPa for expansion up toabout the original length or radius of material.

In some embodiments, the expandable conduit may be composed of multiplematerials. For example, the conduit may be composed of a material havinga first yield strength and first ultimate tensile strength and may beimpregnated with a second material having a second yield strength and/orsecond ultimate tensile strength. In an additional non-limiting example,the conduit may be fabricated from two or more elastic or plasticallydeformable materials woven together.

In embodiments in which the expandable conduit includes more than onelayer of material, each layer of a multi-layer conduit may be composedof the same material. In other embodiments, each layer of a multi-layerconduit may be composed of a different material. In further embodiments,each layer of a multi-layer conduit may be composed of a materialcharacterized by different mechanical properties. For example, an innerlayer of a multi-layer conduit may include a material having a firstyield strength and first ultimate tensile strength and an outer layerthat may include a second material having a second yield strength and/orsecond ultimate tensile strength. The first yield strength may begreater than, about equal to, or less than the second yield strength.The first ultimate tensile strength may be greater than, about equal to,or less than the second ultimate tensile strength. Alternatively, aninner layer may include an elastic or plastically deformable materialand an outer layer may include an inelastic or frangible material.

Conduits composed of multiple layers may have expansion capabilitiesdepending on the material properties of the multiple layers. Forexample, a conduit composed of a biodegradable outer layer and anelastic or plastically deformable inner layer may be expanded due to theforce of a fluid flowing therein but only after the outer layer hasdegraded. In another example, a conduit having an inelastic or frangibleouter layer and an elastic or plastically deformable inner layer mayremain in an unexpanded state until sufficient force, for examplesupplied by an inserted expansion device, is applied internally torupture the outer layer and thus permit the inner layer to expand.

It may be understood that the conduit materials, formulations, and/ormechanical properties may be constant over the longitudinal dimension ofthe conduit. Alternatively, the conduit materials, formulations, and/ormechanical properties of the conduit may vary along the length or anypartial length of the conduit. Conduits having multiple branches mayhave mechanical properties that differ between the branches and/or amain cylindrical tube of the conduit.

In some examples, the conduit may form a generally cylindrical tube. Inother examples, the conduit may have a more complex geometry includinghaving branches. In some examples, the conduit may form a maincylindrical tube along a partial length of the conduit and then branchinto two or more tubular portions. In alternative examples, the conduitmay form a main cylindrical tube along the length of the conduit withtubular portions extending from the main cylindrical tube. It may beunderstood that a conduit disclosed as being composed of a “cylindricaltube” may include any number of bends, kinks, or other deformationsalong the longitudinal axis of the cylindrical tube.

The conduit may generally be any size or shape, including having apre-expansion inner diameter greater than or equal to about 2 mm andless than about 20 mm. Examples of such pre-expansion inner diameter mayinclude, without limitation, about 2 mm, about 4 mm, about 6 mm, about 8mm, about 10 mm, about 15 mm, about 20 mm, and ranges between any two ofthese values (including endpoints). In some other examples, the conduitmay have a pre-expansion inner diameter greater than or equal to about 4mm and less than about 14 mm. Examples of such pre-expansion innerdiameter may include, without limitation, about 4 mm, about 6 mm, about8 mm, about 10 mm, about 12 mm, about 14 mm, and ranges between any twoof these values (including endpoints). After expansion, the conduit mayhave an inner diameter greater than or equal to about 8 mm and less thanabout 24 mm. In other examples, after expansion, the conduit may have aninner diameter greater than or equal to about 4 mm and less than about34 mm. Examples of such post-expansion inner diameter may include,without limitation, about 4 mm, about 6 mm, about 8 mm, about 10 mm,about 15 mm, about 20 mm, about 25 mm, about 30 mm, about 34 mm, andranges between any two of these values (including endpoints). In someexamples, the expandable conduit may be fabricated from a plasticallydeformable material having a thickness of about 0.01 mm to about 2 mm.In some examples, the conduit may have a wall thickness greater than orequal to about 10 μm and less than about 2000 μm. In other non-limitingexample, the conduit may have a wall thickness of about 100 μm to about1000 μm. Examples of such conduit wall thickness may include, withoutlimitation, about 10 μm, about 20 μm, about 50 μm, about 100 μm, about200 μm, about 500 μm, about 1000 μm, about 2000 μm, and ranges betweenany two of these values (including endpoints).

In some alternative embodiments, the mechanical properties of theexpandable conduit may be about equal in or may differ between thelongitudinal dimension and the radial dimension. In one example, anexpandable conduit may have a first yield strength along thelongitudinal dimension greater than 0.2 MPa, and a second yield strengthalong the radial dimension greater than 0.2 MPa. In an alternativeexample, the first yield strength in a longitudinal dimension of aconduit may be greater than about 10 MPa and the second yield strengthin a radial dimension of the conduit may be greater than about 2.75 MPa.

In certain embodiments, the conduits described above may includeadditional components. For example, in some embodiments, the conduitsmay include a stent that is attached to or encapsulated by the materialmaking up the conduit, or an inner layer may include a stent while anouter layer may include an elastic or plastically deformable material.In yet another example, a conduit may be composed of a biodegradableouter layer and an elastic or plastically deformable inner layer. Insome further examples, a multi-layer expandable conduit may include afirst inner layer comprising a woven material and a second outer layercomprising a woven material. It may be understood that the wovenmaterial composing the inner layer may be the same as the woven materialcomposing the outer layer. Alternatively, the woven material composingthe inner layer may differ from the woven material composing the outerlayer.

Although disclosed above are conduits composed of a variety of materialsand having a variety of mechanical properties associated therewith, itmay be appreciated that such materials and properties may equally applyto conduits comprising a valve structure (hereafter, a valved conduit).In addition to valve structures, such implantable conduits may includeone or more sinus bulge geometries. In some examples, a valved conduitmay include one or more sinus bulges in a proximal (upstream to flow)portion with respect to a valve structure. Alternatively, a valvedconduit may include one or more sinus bulges in a distal (downstream toflow) portion with respect to a valve structure. Such sinus bulgegeometries included in a valved conduit may be fabricated due to theapplication of heat and/or pressure to at least a portion of theconduit. It may be further understood that a valved conduit composed ofmultiple layers may have the valve structure associated with aninner-most layer. Such valved conduits may also find use forimplantation in animals for veterinary purposes.

FIG. 1 depicts a cross sectional view of an expandable valved conduitthat may be implantable in an animal or human, according to onenon-limiting example. The expandable valved conduit may include aconduit 110 constructed of synthetic material and a valve structure 120.The valve structure 120 may include one or more leaflet elements 125 a,125 b contained within the conduit 110. Each of one or more leafletelements 125 a, 125 b may have one or more free edges capable of motionand one or more edges which may be in mechanical communication with theconduit 110. In some non-limiting examples, the edges in mechanicalcommunication with the conduit 110 may be affixed to an inner conduitsurface.

FIGS. 2A and 2B depict a cross section view of an example of anexpandable valved conduit; FIG. 2A depicts the valved conduit in an openstate, and FIG. 2B depicts the valved conduit in a closed state that mayresult in closing of the majority of the valve's open orifice area whileretaining an open gap area.

Both FIGS. 2A and 2B illustrate a conduit 210 including a valvestructure 220 therein. In the non-limiting example depicted in FIGS. 2Aand 2B, the valve structure 220 may be composed of two leaflets 225 aand 225 b. It may be understood that alternative embodiments of a valvestructure 220 may include one leaflet, three leaflets, or any number ofleaflets. FIG. 2A depicts the valved conduit in an open state in whichthe valve leaflets 225 a and 225 b may be separated by some distance andmay additionally lie at least in part along the inner surface of theconduit 210 due the force of fluid flow. In the open state, the valveleaflets 225 a and 225 b may be disposed to provide an open orifice areatherebetween that may have an orifice area almost the same as thecross-sectional area of the conduit 210.

FIG. 2B depicts the valved conduit in a closed state. In the closedstate, the valve leaflets 225 a′ and 225 b′ may be proximate to eachother. In some non-limiting embodiments, the valve leaflets 225 a′ and225 b′ may lie edge-to-edge with each other. In some other non-limitingembodiments, the valve leaflets 225 a′ and 225 b′ may at least partiallyoverlap each other. In some other non-limiting embodiments, the valveleaflets 225 a′ and 225 b′ may be domed or partially domed. FIG. 2Billustrates other possible features associated with the valve structure220. Such additional features may include a commissure 230 joiningtogether at least a part of the valve leaflets 225 a′ and 225 b′, and agap 235 between at least one free edge of at least one leaflet (225 a′,225 b′, or both) and an inner surface of the conduit 210.

In general, a valve structure incorporated in a valved conduit may beconstructed of the same material as those comprising the conduit,including, without limitation, a plastically deformable material, anelastic material, a non-deformable material, or mixtures thereof. Insome examples, the valve structure may be composed of the same materialsand have the same mechanical properties as the conduit. In some otherexamples, the valve structure may be composed of the same material asthe conduit but have mechanical properties differing from those of theconduit. In some additional examples, the valve structure may becomposed of materials that differ from those of the conduit. In oneexample, the conduit, valve structure, or both conduit and valvestructure may be made of a polymer which has been coated with ananti-coagulant material. In some additional examples, the conduit, valvestructure, or both conduit and valve structure may incorporatebio-active coatings.

In another embodiment, the valved conduit may include a conduit having afirst conduit layer having an inner surface in physical communicationwith an outer surface of a second conduit layer and a valve structure isdisposed within the second conduit layer. As one example of such amulti-layer valved conduit, the first conduit layer may be composed of afirst plastically deformable material having a yield strength of about0.1 MPa to about 4 MPa, and the second conduit layer may be composed ofthe same plastically deformable material as the first layer. In analternative example, the multi-layer valved conduit may be composed of afirst conduit layer having a first plastically deformable materialhaving a yield strength of about 0.1 MPa to about 4 MPa, and a secondconduit layer composed of a second material that may differ from thefirst material. In still another example, the valved conduit may have afirst conduit layer composed of a woven material, a second conduit layercomposed of a woven material, or both the first conduit layer and thesecond conduit layer may each be composed of a woven material. In someembodiments of the multi-layer valved conduit, the first conduit layermay be biodegradable. In some alternative embodiments of a multi-layervalved conduit, the first conduit layer may include a non-plasticallydeformable material. In yet another embodiment, the multi-layer valvedconduit may include a stent as part of the second conduit layer.

In order to ensure that proper valve function is maintained throughoutthe lifetime of the conduit, including expansion, acomputer-optimization routine is disclosed herein that may accuratelyand precisely simulate the geometry of different valve leaflet designsin varying positions and throughout different stages of conduitexpansion. These leaflet geometries can be simulated under physiologicflow conditions through the use of computation fluid dynamics. Based onsuch simulations, an optimal leaflet may be designed to minimizeregurgitation during ventricular diastole and maximize open orifice areaduring ventricular systole throughout the lifetime of the conduit.

Valve structures incorporated into valved conduits may be designed basedat least in part on modeling/optimization algorithms embodied in acomputing device. Such algorithms may be used to design valve structurescapable of meeting one or more acceptance criteria regarding fluid flowthrough the valved conduit as the conduit radially enlarges. In oneexample, the modeling/optimization algorithms may use physical data fromactual patients who might require the conduit. Thesemodeling/optimization algorithms may include Computational FluidDynamics (CFD), solid-mechanics modeling, and other optimizationroutines. Acceptance criteria may include measures of fluid turbulence,regurgitation, and other dynamic parameters of the fluid flow throughthe valve structure as the conduit radially enlarges and the valvestructure changes position within the conduit. Additional parametersrelated to structural components of the valved conduit may include thearea of the valve structure orifice when in the open configuration, thefluid volume flow through the open valve structure, and a measurerelated to the physical contact of valve structure leaflets and an innersurface of the conduit.

In one embodiment, modeling and/or optimization calculations may be usedto reduce diastolic flow regurgitation through a heart valve structure,as well as to improve effective orifice area and overall heart valvestructure function. In one non-limiting embodiment, a heart valveleaflet structure modeling program may predictively generate one or moreheart valve leaflet structure models based, at least in part, ongeometric parameters and solid-mechanics principals. In anothernon-limiting embodiment, one or more solid heart valve leaflet structuremodels may be analyzed according to one or more fluid flow analyticalmethods. For example, FIG. 3A depicts a mesh-structure model of a heartvalve leaflet generated by a solid mechanical simulation algorithm; FIG.3B depicts a solid model constructed from the mesh-structure in FIG. 3A.

Non-limiting examples of such fluid flow analytical methods may includefluid-structure interaction (FSI) and computational fluid dynamics (CFD)simulations. In a non-limiting embodiment, an iterative optimizationmethod for generating heart valve leaflet structure models may include:(1) calculating a heart valve leaflet structure model based on a set ofparameters including one or more geometric parameters; (2) analyzing aperformance of the heart valve leaflet structure model based at least inpart on one or more fluid flow analytical methods; (3) calculating aperformance cost function according to data calculated by the one ormore fluid flow analytical methods; and (4) varying one or more of theheart valve leaflet structure modeling parameters in a manner tominimize the value of the valve performance cost function.

Mathematical modeling and/or optimization calculations that may be usedto calculate shapes and/or dimensions of heart valve leaflet structuresmay include, without limitation, computational fluid dynamics (CFD),solid-mechanics modeling, fluid/structure interaction (FSI) modeling,and blood-flow optimization algorithms. Calculations based on CFD modelsmay show a difference in blood flow velocity based on a curvature of theconduit component of a heart valve structure. FIG. 4 depicts an exampleof such a flow-velocity simulation. For example, a blood flow model mayindicate greater flow along a conduit axis having a large radius ofcurvature as opposed to the blood flow in a conduit having a smallerradius of curvature. CFD models, for example, may provide data tosuggest that a curved conduit should not have a heart valve leafletstructure at the conduit bottom as a heart valve leaflet structure lowerleaflet may become stuck at the closing phase, thereby leading tothrombosis.

Mathematical calculations and/or optimization calculations may becarried out, for example, by means of one or more computing devices.Such computing devices may include, without limitation, one or more ofthe following: central processor units, numerical accelerators, staticand/or dynamic memories, data storage devices, data input devices, dataoutput devices, communication interfaces, and visual displays. While asingle computing device may be used for such calculations, multiplecomputing devices, for example in a shared network or cloudconfiguration, may also be used. It may be appreciated that the one ormore computing devices may operate independently or in concert. Inaddition, communications between one or more users and one or morecomputing devices may occur over one or more input interface device,including, without limitation, a keyboard, a mouse, a track-ball, astylus, a voice recognition system, and/or a touch pad display. Inaddition, the one or more computing devices may provide outputinformation to the one or more users by one or more output interfacedevice, including, without limitation, a visual display, a printer,and/or an audio interface. Data communication between computing devicesmay occur over one or more computing system communication interface,including, but not limited to, a serial interface, a parallel interface,an Ethernet interface, a wireless interface, and/or an opticalinterface. Additional communications between computing devices, orbetween computing devices and users, may be accomplished over one ormore computing system communication protocols including, but not limitedto, a personal area networks (such as BlueTooth), a local area network,a wide area network, and/or a satellite network.

FIG. 5 is a flow chart illustrating an embodiment of a method fordesigning an implantable valved conduit composed of a plasticallydeformable material.

Initially, valved conduit modeling parameters may be provided 500 to thesolid-mechanics modeling algorithm, the parameters including datarelated to the anatomy or physiology of the recipient patient. Examplesof such anatomic and/or physiologic data may include a pressure acrossthe valve structure within the valved conduit, a fluid flow rate throughthe valved conduit, and physical measurements of vascular structures towhich the valved conduit may be attached. An initial radial dimension ofthe valved conduit to be modeled may also be provided 505. Further, datarelated to the expandability of the plastically deformable material maybe provided to the model. Such data may include a yield strength,ultimate tensile strength, elastic modulus, and other mechanicalproperties of the plastically deformable material. Additionally, ameasure of expected patient anatomic growth, or changes to the patientphysiology as a response of patient growth, may be determined. Theexpected patient growth information, along with the data related to theplastic deformability of the valved conduit material, may be used toestimate a desired amount of expandability for the valved conduit. Suchexpandability data may be provided 510 to the modeling software as oneor more expansion measurements for the conduit.

Physical parameters associated with the initially defined valvestructure may be provided to the modeling software as well. Suchphysical parameters may include, without limitation, a conduit lengthand a conduit wall thickness. Additional physical parameters may beprovided to the modeling software that relate to physical dimensions ofthe valve structure. Some examples of such physical dimensions may berelated to the shape and size of valve leaflets that may comprise thevalve structure. Non-limiting examples of valve leaflet physicalparameters may include one or more of a sinus edge shape, a sinus edgeperimeter length, a fan edge shape, a fan edge perimeter length, aheight, a fan structure height, a baseline width, and a commis surelength. A valve structure modeling computation may then create aninitial mathematical model of the initial valved conduit related to thephysical and mechanical properties of the valved conduit as initiallydefined.

The initial model representing the initial valved conduit may then beused in a fluid flow simulation algorithm to determine thecharacteristics of fluid flow through the initial valved conduit. One ormore one or more initial fluid flow metrics including, withoutlimitation, a fluid velocity profile, a fluid pressure profile, and afluid volumetric flow profile may then be calculated 515 by the fluidflow simulation algorithm. One or more plastic deformabilitycharacteristics of the material may also be used in such a fluid flowsimulation algorithm in addition to the anatomic and/or physiologicaldata from a patient, the initial proposed radial dimension of theconduit, and physical metrics associated with the valve structure.

Once the initial fluid flow metrics have been calculated 515, theinitial mathematical model representing the initial valved conduit maybe altered to provide at least a second mathematical model representingat least a second valved conduit. The at least second valved conduitmodel may differ from the initial valved conduit model in a variety ofways, including, but not limited to, radial dimension of the conduit,valve leaflet physical parameters, expansion measurements of thematerial, and one or more measures related to the plasticity propertiesof the material (such as a change in stress or strain characteristics ofthe materials). One or more second fluid flow metrics may then becalculated 520 by the fluid flow simulation algorithm based on the atleast second model of the valved conduit.

It may be appreciated that the fluid flow simulation algorithm may besequentially applied to additional valved conduit models, eachsucceeding model representing a succeeding valved conduit that has beenaltered in some manner from a preceding valved conduit. Thus, forexample, a series of valved conduits may be modeled that may differ onlyin their conduit radial dimensions. Such a series may represent a radialchange of an implanted valved conduit over time as the patient grows andthe conduit expands to accommodate the patent growth. The change inradial dimension of the valved conduit over time may be simulated by thefluid flow simulation algorithm as a change in the fluid flow metricsassociated with each succeeding conduit configuration analyzed thereby.

Once a sequence of fluid flow metrics have been obtained, including theinitial fluid flow metric and the at least second fluid flow metric, adeformation metric may be calculated 525. The deformation metric may becalculated from the multiplicity of fluid flow metrics in any number ofways, including, without limitation, an arithmetic mean of fluid flowmetrics, a geometric mean of fluid flow metrics, a harmonic mean offluid flow metrics, or a weighted average of fluid flow metrics. Aweighted average of fluid flow metrics may be calculated as a sum offluid flow metrics, each weighted by some weighting factor. In onenon-limiting example, a weighting factor may be derived from a flowefficiency metric or cost function associated with the effectiveness offluid flow through a valved conduit structure having a particular set ofcharacteristics, such as radial dimension. Efficiency may be based on afluid flow rate, an open area within the valve structure during flow, ora measure of regurgitant flow.

At the completion of the optimization calculations, a valved conduit maybe fabricated 530 from the plastically deformable material usingphysical characteristics of the conduit and valve structure as suppliedto the initial model of the valved conduit if the calculated deformationmetric is greater than or equal to an acceptance value. Somenon-limiting examples of such acceptance values may incorporate valuescalculated for one or more of a regurgitation fraction, an open orificearea, and a percent leaflet/wall contact measure. A regurgitationfraction may measure the ratio of fluid back-flow through a valve in aclosed state to the fluid forward-flow through the valve in an openstate. An open orifice area may be calculated at a percent of across-sectional area of the conduit lumen not occluded by the valvestructure when the valve structure is in an open position. An additionalmeasure of conduit patency may include a measure of the fraction of avalve structure leaflet in contact with an inner surface of the conduit(compared to total leaflet area). Some examples of an acceptance valuemay include a regurgitation fraction less than or equal to about 30%, anopen orifice area greater than or equal to about 80%, or a leaflet/wallcontact value of less than or equal to about 15%.

While an implanted valved conduit fabricated from a plasticallydeformable material may be able to expand as the patient grows, therebyproviding some long term treatment, it may be possible that a singleplastically deformable valved conduit may not be sufficient to assist apatient from neonatal size to full adult size. In such an instance, itmay be necessary to replace an initial valved conduit with a secondvalved conduit capable of expanding from an intermediate patient age tofull adulthood. A plastically deformable valved conduit may be replacedin situ without the need for excising the original and replacing it witha second valved conduit.

FIG. 6 is a flow chart of one method that may be used to replace animplanted first expandable valved conduit with a second expandablevalved conduit.

As disclosed above, a first expandable valved conduit may be unable toassist a patient after some period of patient growth. In onenon-limiting example, the conduit may radially enlarge to an extent thatthe valve structure may no longer efficiently regulate blood flow. Thefirst valved conduit may not have expanded to its fully expanded statewhen valve structure inefficiency may become apparent. Under suchconditions, the first valved conduit may be replaced by a second valvedconduit by introducing the second valved conduit within the first valvedconduit and expanding the second in situ. Specifically, an expansiondevice, such as a balloon catheter, may be introduced into thevasculature so that the expansion device contacts 600 an inner surfaceof the first valved conduit. The expansion device may then be expanded610 within the first valved conduit thereby radially increasing at leasta portion of the first valved conduit. A second valved conduit may thenbe introduced 620 within at least a portion of the expanded first valvedconduit. The second valved conduit may be introduced using the sameexpansion device as used to expand the first valved conduit while thefirst valved conduit is expanded. Alternatively, the second valvedconduit may be introduced 620 by the use of an alternative device. Oncethe second valved conduit has been emplaced, the second valved conduitmay also be expanded 630 to provide a valve structure capable ofregulating fluid flow through the conduit.

EXAMPLES Example 1: A First Plastically Deformable Material Usable in anImplantable Conduit

FIG. 7A depicts the stress/strain curve of a first plasticallydeformable material that may be used to fabricate a plasticallydeformable and implantable conduit. The material has an average yieldstrength of about 2.1 MPa and an ultimate tensile strength of about 5MPa. The material further demonstrates elastic deformation below theyield strength, characterized by an average elastic modulus of about 5.9MPa. At the section of the stress/strain curve where the materialtransitions from the elastically deformable mode to the plasticallydeformable mode, the material demonstrates an average 36% elongationabove the original length at the yield stress point. Such a material maybe favorably used for a plastically deformable conduit capable ofexpanding to meet the needs of a growing anatomical structure due to theextended region of the stress/strain curve indicating plasticdeformability as opposed to elastic deformability.

Example 2: A Second Plastically Deformable Material Usable in anImplantable Conduit

FIG. 7B depicts the stress/strain curve of a second plasticallydeformable material that may be used to fabricate a plasticallydeformable and implantable conduit. The material demonstrates an averageyield strength of about 1.7 MPa and an ultimate tensile strength ofabout 5.5 MPa. The material also has a region of elastic deformationbelow the yield strength characterized by an average elastic modulus ofabout 7.4 MPa. At the section of the stress/strain curve where thematerial transitions from the elastically deformable mode to theplastically deformable mode, the material demonstrates an average 24%elongation above the original length at the yield stress point. Such amaterial may be favorably used for a plastically deformable conduitcapable of expanding to meet the needs of a growing anatomical structuredue to the extended region of the stress/strain curve indicating plasticdeformability as opposed to elastic deformability.

The present disclosure is not to be limited in terms of the particularembodiments described in this application, which are intended asillustrations of various aspects. Many modifications and variations canbe made without departing from its spirit and scope, as will be apparentto those skilled in the art. Functionally equivalent methods andapparatuses within the scope of the disclosure, in addition to thoseenumerated in this disclosure, will be apparent to those skilled in theart from the foregoing descriptions. Such modifications and variationsare intended to fall within the scope of the appended claims. Thepresent disclosure is to be limited only by the terms of the appendedclaims, along with the full scope of equivalents to which such claimsare entitled. It is also to be understood that the terminology used inthis disclosure is for the purpose of describing particular embodimentsonly, and is not intended to be limiting.

With respect to the use of substantially any plural and/or singularterms in this disclosure, those having skill in the art can translatefrom the plural to the singular and/or from the singular to the pluralas is appropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth in thisdisclosure for sake of clarity. It will be understood by those withinthe art that, in general, terms used in this disclosure, and especiallyin the appended claims (e.g., bodies of the appended claims) aregenerally intended as “open” terms (e.g., the term “including” should beinterpreted as “including but not limited to,” the term “having” shouldbe interpreted as “having at least,” the term “includes” should beinterpreted as “includes but is not limited to,” etc.).

It will be further understood by those within the art that if a specificnumber of an introduced claim recitation is intended, such an intentwill be explicitly recited in the claim, and in the absence of suchrecitation no such intent is present. For example, as an aid tounderstanding, the following appended claims may contain usage of theintroductory phrases “at least one” and “one or more” to introduce claimrecitations. However, the use of such phrases should not be construed toimply that the introduction of a claim recitation by the indefinitearticles “a” or “an” limits any particular claim containing suchintroduced claim recitation to embodiments containing only one suchrecitation, even when the same claim includes the introductory phrases“one or more” or “at least one” and indefinite articles such as “a” or“an” (e.g., “a” and/or “an” should be interpreted to mean “at least one”or “one or more”); the same holds true for the use of definite articlesused to introduce claim recitations. In addition, even if a specificnumber of an introduced claim recitation is explicitly recited, thoseskilled in the art will recognize that such recitation should beinterpreted to mean at least the recited number (e.g., the barerecitation of “two recitations,” without other modifiers, means at leasttwo recitations, or two or more recitations). It will be furtherunderstood by those within the art that virtually any disjunctive wordand/or phrase presenting two or more alternative terms, whether in thedescription, claims, or drawings, should be understood to contemplatethe possibilities of including one of the terms, either of the terms, orboth terms. For example, the phrase “A or B” will be understood toinclude the possibilities of “A” or “B” or “A and B.”

As will be understood by one skilled in the art, for any and allpurposes, such as in terms of providing a written description, allranges disclosed in this disclosure also encompass any and all possiblesubranges and combinations of subranges thereof. As will also beunderstood by one skilled in the art all language such as “up to,” “atleast,” and the like include the number recited and refer to rangeswhich can be subsequently broken down into subranges as discussed above.Finally, as will be understood by one skilled in the art, a rangeincludes each individual member.

From the foregoing, it will be appreciated that various embodiments ofthe present disclosure have been described for purposes of illustration,and that various modifications may be made without departing from thescope and spirit of the present disclosure. Accordingly, the variousembodiments disclosed are not intended to be limiting, with the truescope and spirit being indicated by the following claims.

1.-22. (canceled)
 23. A method of replacing a first valved conduitcomprising a plastically deformable material implanted in an animal, themethod comprising: contacting an inner surface of the first valvedconduit with an expansion device; causing the expansion device toexpand, thereby radially increasing at least a portion of the firstvalved conduit; introducing a second valved conduit within at least aportion of the first valved conduit; and causing the second valvedconduit to expand within the at least portion of the first valvedconduit, wherein the plastically deformable material has a yieldstrength of about 0.1 MPa to about 4 MPa and an ultimate tensilestrength greater than about 4 MPa.
 24. An implantable device forimplantation into a human or animal, the implantable device comprising:a fluoropolymer conduit having radial expandability in a range from 20%to 400% above an initial conduit radius, wherein the fluoropolymerconduit is configured to expand upon exertion of a balloon catheter, theballoon catheter having a pressure greater than about 0.05 MPa.
 25. Theimplantable device of claim 24, wherein the fluoropolymer conduitsfurther comprises a valve structure.
 26. The implantable device of claim24, wherein the fluoropolymer conduit comprises at least a first layerand a second layer.
 27. The implantable device of claim 24, where thefluoropolymer conduit has an ultimate tensile strength greater than 4MPa and an internode distance of 10 microns to 60 microns.
 28. A valvedconduit for implantation into a human or animal, the valved conduitcomprising: a fluoropolymer conduit having radial expandability in arange from 20% to 400% above an initial conduit radius; and a valvestructure disposed therein, wherein the fluoropolymer conduit expandsupon exertion of a balloon catheter, the balloon catheter having apressure greater than about 0.05 MPa.
 29. The valved conduit of claim28, wherein the fluoropolymer conduit comprises at least a first layerand a second layer.
 30. The valved conduit of claim 29, wherein thesecond conduit layer comprises a stent.
 31. The valved conduit of claim28, wherein the valve structure comprises one or more leaflets.
 32. Amethod of expanding a device implanted in a human or animal, the methodcomprising: contacting an inner surface of a fluoropolymer conduit withan expansion device; causing the expansion device to expand to apressure greater than about 0.05 MPa, thereby radially increasing atleast a portion of the conduit; increasing the radial expandability in arange from 20% to 400% above an initial conduit radius, wherein theconduit has a yield strength of 0.1 MPa to 4 MPa.
 33. The method ofclaim 32, wherein the fluoropolymer conduits further comprises a valvestructure.